Voltage-activated potassium channels are membrane proteins that critically regulate electrical signalling in neurons. Genetically, they are members of a superfamily of voltage activated channels that includes sodium and calcium channels, other important signalling components. All three types of channels are targets for both toxic and therapeutic drugs, including, for instance, local anesthetic drugs. While the many genes coding for these channels have been cloned and the protein sequence has been determined, many questions remain about how the various channel proteins perform their specific tasks: What distinguishes one type of channel from the other? What parts of the channel protein permit the rapid yet selective movement of potassium ions across the membrane? What parts of the channel protein control and regulate the flow of ions in response to voltage signals? These questions can be addressed by the method of site-directed mutagenesis. By using molecular biological methods to alter the genetic information determining the protein structure, specific amino acids in the channel protein can be modified, and the effect on function assessed. The altered genetic information is expressed in cultured cells. The electrical recording methods of voltage-clamp and single-channel recording are used to assess the effects of specific mutations on function. A program of mutagenesis is proposed to identify specific amino acid residues in the potassium channel protein that affect the binding of small inhibitor molecules. Since there is good evidence that these inhibitors bind within or very close to the ion-selective pore of the potassium channel, such mutations will also be studied for their effect on ion permeation through the pore. Ultimately, these studies should provide insight into the molecular basis of ion selectivity of the voltage-activated channels. Biophysical studies with quaternary ammonium inhibitors of the channel have shown a close relationship between the voltage-dependent gating process and ionic binding to the pore. The mechanistic basis of this relationship will be determined by studies on both wild-type and mutant potassium channels. This work should enhance the understanding of the physical mechanism by which movements through potassium channels are gated.